Systemic lupus erythematosus (SLE) is an autoimmune disease mediated by the production of pathogenic[unreadable] autoantibodies. As with many autoimmune disorders, the factors that contribute to SLE are complex, but it is[unreadable] clear that genetics, environment and gender contribute to disease susceptibility and pathogenesis. For decades[unreadable] it has been speculated that the sex hormone estrogen contributes to the increased occurrence of SLE in[unreadable] females. A recently completed clinical study demonstrated that SLE patients receiving hormone replacement[unreadable] therapy experienced significantly more flares than patients receiving placebo, thus, providing clear evidence[unreadable] that estrogen can exacerbate disease in some patients. Since little is known about the immunomodulatory[unreadable] effects of estrogen, we have been studying the effects of estrogen administration on B cell tolerance. Our[unreadable] laboratory have shown that administration of 17 beta-estradiol into nonautoimmune BALB/c mice that harbor[unreadable] the R4A transgene for the heavy chain of a pathogenic anti-DNA antibody results in the loss of B cell[unreadable] tolerance and induces a lupus phenotype in these mice.[unreadable] To further understand how estrogen alters B cell tolerance, we have obtained mice with targeted deletions in[unreadable] the estrogen receptor genes. To date, two estrogen receptors (ER), ERalpha and ERbeta, have been identified.[unreadable] When bound by estrogen, these receptors act as transcription factors to induce the expression of numerous[unreadable] gene products. The functional distinctions between ERalpha and ERbeta remain to be elucidated, but there is[unreadable] evidence that they may differ in gene activation. Since B cells express both ERalpha and ERbeta, we hypothesize[unreadable] that B cells are directly estrogen responsive and the that activation of these receptors by estrogen induces a[unreadable] genetic program that alters B cell tolerance. From these studies we will determine if one or both estrogen[unreadable] receptors affects the selection, survival and activation of autoreactive B cells and whether these receptors act[unreadable] in a synergistic or antagonistic manner. Results from these studies have important clinical implications since[unreadable] selective estrogen receptor modulators can potentially be developed that act as clinically focused therapeutic[unreadable] agents in lupus patients with an estrogen exacerbated disease.